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Paper of the Month: Discovery of a therapeutic target in Fanconi anemia

"The work reported by this team of researchers is a beautiful example of how a deep understanding of the molecular and genetic underpinnings of a disease phenotype can lead to the identification of novel targets that hold great therapeutic promise in the treatment of a rare disease."

- Mary Stenzel-Poore, PhD

This month's featured paper is from the Grover Bagby Lab, and is titled, "p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes." It waspublished in the journal Blood. The research in this paper was conducted by scientists in the OHSU Department of Medicine, OHSU Doernbecher Children's Hospital, OHSU Knight Cancer Institute and colleagues, and The Gaslini Children's Hospital in Genoa, Italy.The work was funded by a Program Project Grant Award from the National Heart Lung and Blood Institute of the NIH.*

Discovery of a therapeutic target in Fanconi anemia

Fanconi anemia is a rare inherited disease that predisposes children and adults to the development of bone marrow failure, leukemia and cancer. Genetically, the disease results from the inheritance of mutant forms of any given Fanconi gene, of which there are at least fifteen. The disease has an incidence of 1 per 350,000 births.

"Cells in the body of patients with Fanconi anemia are chromosomally unstable," said Grover Bagby, MD, Professor, Departments of Medicine and Molecular and Medical Genetics, "especially when exposed to specific chemicals and chemotherapeutic agents known as DNA cross linking agents."

Once the normal versions of the Fanconi genes were identified, it was no surprise when many investigators worldwide discovered that the proteins they encoded played a role in protecting DNA from damage inflicted upon it by such agents.

While many research teams simply assumed that the entire complex of signs and symptoms of Fanconi anemia were the direct result of DNA damage, The Bagby team felt that this question needed to be answered directly.That is, do all signs of Fanconi anemia occur simply because of ongoing DNA damage?"If it were that simple," said Dr. Bagby, "a whole host of organ systems should be at risk for failure and this is not at all the case."In particular, the bone marrow and blood system seemed to be uniquely affected.

More than 10 years ago, scientists in the Bagby Lab demonstrated that the Fanconi anemia proteins were, in fact, multifunctional. That is, while the proteins protected the genome they likewise participated in biochemical pathways that control the replication and survival of hematopoietic stem cells and progenitor cells.

"We discovered replication and survival of hematopoietic stem cells from mice with Fanconi anemia was markedly suppressed by inflammatory cytokines including one known as tumor necrosis factor alpha (TNF)," said Dr. Bagby. "Even more remarkably, treatment of Fanconi stem cells and their progeny with TNF in culture sometimes gave rise to leukemic stem cells while such treatment of normal cells did not. So TNF may serve as a factor in the selective outgrowth of leukemic clones."

Dr. Bagby's team also found that the white blood cells produced by the Fanconi stem cells produced too much TNF when stimulated with certain molecules known as Toll-Like-Receptor agonists. In effect, progeny of the mutant stem cells made too much of precisely the same protein that delivered the knockout punch to the stem cells themselves and facilitated the emergence of leukemia.

Seeking to disrupt this pernicious signaling loop, the team sought to discover small molecules that suppressed the production of TNF in Fanconi anemia cells. "We screened over 100 pharmacological agents and identified an inhibitor of a protein called p38 MAP kinase that was highly effective in suppressing the production of TNF," said Dr. Bagby. "Then we defined the general mechanism by which this agent worked in these mutant cells and confirmed that the agent also worked to correct the TNF-production abnormality in white cells from children with the two most common forms of Fanconi anemia."

Because other labs have determined that this category of drug may enhance stem cell function in Fanconi anemia patients, Dr. Bagby's team is currently planning to test the capacity of these agents to correct bone marrow failure in mice with Fanconi anemia without increasing the risk of leukemia.If it can be done, Dr. Bagby said his team will move to the development of a clinical trial for children and adults with Fanconi anemia, a trial that will use one agent in an attempt to improve bone marrow function and prevent leukemia.

ABOUT THE PAPER OF THE MONTH

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD.